Genome-wide comparative analysis of atopic dermatitis and psoriasis gives insight into opposing genetic mechanisms

Hansjörg Baurecht; Melanie Hotze; Stephan Brand; Carsten Büning; Paul Cormican; Aiden Corvin; David Ellinghaus; Eva Ellinghaus; Jorge Esparza-Gordillo; Regina Fölster-Holst; Andre Franke; Christian Gieger; Norbert Hubner; Thomas Illig; Alan D Irvine; Michael Kabesch; Young A E Lee; Wolfgang Lieb; Ingo Marenholz; W H Irwin McLean; Derek W Morris; Ulrich Mrowietz; Rajan Nair; Markus M Nöthen; Natalija Novak; Grainne M O'Regan; Psoriasis Association Genetics Extension; Stefan Schreiber; Catherine Smith; Konstantin Strauch; Philip E Stuart; Richard Trembath; Lam C Tsoi; Michael Weichenthal; Jonathan Barker; James T Elder; Stephan Weidinger; Heather J Cordell; Sara J Brown

doi:10.1016/j.ajhg.2014.12.004

Genome-wide comparative analysis of atopic dermatitis and psoriasis gives insight into opposing genetic mechanisms

Am J Hum Genet. 2015 Jan 8;96(1):104-20. doi: 10.1016/j.ajhg.2014.12.004.

Authors

Hansjörg Baurecht¹, Melanie Hotze¹, Stephan Brand², Carsten Büning³, Paul Cormican⁴, Aiden Corvin⁴, David Ellinghaus⁵, Eva Ellinghaus⁵, Jorge Esparza-Gordillo⁶, Regina Fölster-Holst¹, Andre Franke⁵, Christian Gieger⁷, Norbert Hubner⁸, Thomas Illig⁹, Alan D Irvine¹⁰, Michael Kabesch¹¹, Young A E Lee⁶, Wolfgang Lieb¹², Ingo Marenholz⁶, W H Irwin McLean¹³, Derek W Morris¹⁴, Ulrich Mrowietz¹, Rajan Nair¹⁵, Markus M Nöthen¹⁶, Natalija Novak¹⁷, Grainne M O'Regan¹⁸; Psoriasis Association Genetics Extension; Stefan Schreiber¹⁹, Catherine Smith²⁰, Konstantin Strauch²¹, Philip E Stuart¹⁵, Richard Trembath²², Lam C Tsoi²³, Michael Weichenthal¹, Jonathan Barker²⁰, James T Elder²⁴, Stephan Weidinger²⁵, Heather J Cordell²⁶, Sara J Brown²⁷

Affiliations

¹ Department of Dermatology, Allergology, and Venereology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
² Department of Medicine II - Grosshadern, Ludwig-Maximilians-University (LMU), 81377 Munich, Germany.
³ Department of Gastroenterology, Hepatology and Endocrinology, Charité, Campus Mitte, 10117 Berlin, Germany.
⁴ Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.
⁵ Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany.
⁶ Max-Delbrück-Centrum (MDC) for Molecular Medicine, Berlin-Buch, 13092 Berlin, Germany; Pediatric Allergy, Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany.
⁷ Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Research Unit of Molecular Epidemiology, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany.
⁸ Max-Delbrück-Centrum (MDC) for Molecular Medicine, Berlin-Buch, 13092 Berlin, Germany.
⁹ Research Unit of Molecular Epidemiology, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Hannover Unified Biobank, Hannover Medical School, 30625 Hannover, Germany.
¹⁰ Department of Paediatric Dermatology, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland; National Children's Research Centre, Dublin 12, Ireland; Department of Clinical Medicine, Trinity College Dublin, Dublin 2, Ireland.
¹¹ Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), 93042 Regensburg, Germany.
¹² Institute of Epidemiology and PopGen Biobank, University Hospital Schleswig-Holstein, 24105 Kiel, Germany.
¹³ Dermatology and Genetic Medicine, College of Life Sciences and College of Medicine, Dentistry & Nursing, University of Dundee, Dundee DD1 5EH, UK.
¹⁴ Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland; Cognitive Genetics and Therapy Group, School of Psychology and Discipline of Biochemistry, National University of Ireland, Galway, Ireland.
¹⁵ Department of Dermatology, University of Michigan, Ann Arbor, MI 48109-5675, USA.
¹⁶ Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, 53127 Bonn, Germany.
¹⁷ Department of Dermatology and Allergy, University of Bonn Medical Center, 53105 Bonn, Germany.
¹⁸ Department of Paediatric Dermatology, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland.
¹⁹ Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany; Department of Internal Medicine, University Medical Center Schleswig-Holstein, 24105 Kiel, Germany.
²⁰ Division of Genetics and Molecular Medicine, St John's Institute of Dermatology, Kings College London, London SE1 9RT, UK.
²¹ Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, 80539 Munich, Germany.
²² Queen Mary University of London, Barts and the London School of Medicine and Dentistry, London E1 4NS, UK.
²³ Department of Biostatistics, Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI 48109-5314, USA.
²⁴ Department of Dermatology, University of Michigan, Ann Arbor, MI 48109-5675, USA; Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI 48105, USA.
²⁵ Department of Dermatology, Allergology, and Venereology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany. Electronic address: sweidinger@dermatology.uni-kiel.de.
²⁶ Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
²⁷ Dermatology and Genetic Medicine, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK. Electronic address: s.j.brown@dundee.ac.uk.

Abstract

Atopic dermatitis and psoriasis are the two most common immune-mediated inflammatory disorders affecting the skin. Genome-wide studies demonstrate a high degree of genetic overlap, but these diseases have mutually exclusive clinical phenotypes and opposing immune mechanisms. Despite their prevalence, atopic dermatitis and psoriasis very rarely co-occur within one individual. By utilizing genome-wide association study and ImmunoChip data from >19,000 individuals and methodologies developed from meta-analysis, we have identified opposing risk alleles at shared loci as well as independent disease-specific loci within the epidermal differentiation complex (chromosome 1q21.3), the Th2 locus control region (chromosome 5q31.1), and the major histocompatibility complex (chromosome 6p21-22). We further identified previously unreported pleiotropic alleles with opposing effects on atopic dermatitis and psoriasis risk in PRKRA and ANXA6/TNIP1. In contrast, there was no evidence for shared loci with effects operating in the same direction on both diseases. Our results show that atopic dermatitis and psoriasis have distinct genetic mechanisms with opposing effects in shared pathways influencing epidermal differentiation and immune response. The statistical analysis methods developed in the conduct of this study have produced additional insight from previously published data sets. The approach is likely to be applicable to the investigation of the genetic basis of other complex traits with overlapping and distinct clinical features.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Alleles
Case-Control Studies
Chromosomes, Human, Pair 1 / genetics
Chromosomes, Human, Pair 5 / genetics
Chromosomes, Human, Pair 6 / genetics
Cohort Studies
Comparative Genomic Hybridization*
Dermatitis, Atopic / genetics*
Genetic Loci
Genome-Wide Association Study*
Humans
Logistic Models
Major Histocompatibility Complex / genetics
Polymorphism, Single Nucleotide
Psoriasis / genetics*
Quality Control
Reproducibility of Results

Abstract

Publication types

MeSH terms

Grants and funding